Rilpivirine, chemically 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]pyrimidinyl]amino]benzonitrile and has the structural formula:
                Rilpivirine (TMC278) is an investigational new drug, developed by Tibotec, for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs.        
Rilpivirine and its hydrochloride salt were disclosed in U.S. Pat. No. 7,125,879.
Process for the preparation of rilpivirine was disclosed in U.S. Pat. No. 7,399,856 ('856 patent). According to the '856 patent, rilpivirine can be prepared by
reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride of formula II with 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a in the presence of potassium carbonate and acetonitrile. The synthetic procedure is illustrated in scheme I, below:
According to the '856 patent described a process for the preparation of 4-(4-chloropyrimidin-2-ylamino)benzonitrile, can be prepared by reacting 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile with phosphorus oxychloride in presence of sodium hydroxide and methylene chloride.
U.S. Pat. No. 7,563,922 disclosed a process for the preparation of (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride.
Fumarate salt of rilpivirine and its process were disclosed in U.S. patent application publication no. 2009/215804.
We have found that a novel process for the preparation of 4-(4-chloropyrimidin-2-ylamino)benzonitrile. 4-(4-Chloropyrimidin-2-ylamino)benzonitrile is a key intermediate for the preparation of rilpivirine.
We have also found that a novel process for the preparation of 4-iodo-2,6-dimethyl benzenamine.
We have also found that an improved process for the preparation of rilpivirine.
The processes of present invention are simple, eco-friendly, inexpensive, reproducible, robust and is well suited on an industrial scale.
We have also found that a tosylate salt of rilpivirine.
Thus, one object of the present invention is to provide a novel process for the preparation of 4-(4-chloropyrimidin-2-ylamino)benzonitrile.
Another object of the present invention is to provide a novel process for the preparation of 4-iodo-2,6-dimethyl benzenamine.
Another object of the present invention is to provide an improved process for the preparation of rilpivirine.
Another object of the present invention is to provide a tosylate salt of rilpivirine, process for its preparation and pharmaceutical compositions comprising it.
The tosylate salt of rilpivirine of the present invention may also serve as intermediate for preparation of rilpivirine and its salts.